Abstract Infection with Hepatitis C virus (HCV), an important human blood-borne pathogen, is the most significant risk factor for the development of hepatocellular carcinoma (HCC), a major liver malignancy and cancer type worldwide. Eighty-five percent of HCV infections become chronic with sequelae including fibrosis, cirrhosis and eventually HCC, a highly malignant tumor with current average survival rates of less than 1 year following diagnosis. Currently, there are no prophylactic vaccines against HCV, and although anti-HCV therapies have advanced within the last two years, treatment success has been limited due to relative efficacy of different regimens in different patient populations, adverse drg effects resulting in patient non-adherence, rapid emergence of drug-resistant variants, access to care and cost of therapy. With an estimated 200 million chronically infected individuals world-wide and a reported 350,000 deaths annually, hepatitis C has emerged as a serious global health burden. Therefore, a better understanding of the pathophysiological mechanisms modulating HCV pathogenesis are sorely warranted to address this global crisis and identify new molecular targets. In this application, we will address the role of interferon regulatory facto 5 (IRF5) in HCV pathogenesis mechanisms. IRF5 belongs to the interferon regulatory factor (IRF) family of transcription factors that play critical roles in virus-, IFN- and DNA damage-induced signaling pathways. Recently, new facets of IRF5 in regulating cell growth, apoptosis and tumor suppressor function have emerged. Importantly, IRF5 has now been implicated in several human cancers. Surprisingly, its role in HCV pathogenesis has not been explored to-date. Although IRF5 is normally expressed in hepatocytes, we have discovered that IRF5 expression is dramatically down-regulated in HCV replicon bearing hepatoma cells and further IRF5 over-expression suppresses HCV translation and replication. Importantly, we provide critical evidence that IRF5 suppresses the activity of the oncogene autotaxin (ATX), previously reported as a contributing factor in HCV-associated oncogenesis. This suggests that IRF5 may serve as a negative restriction factor in HCV pathogenesis. These compelling evidences argue in favor of a tumor-suppressive role for IRF5 in HCV replication and pathogenesis. The proposed studies will delineate the molecular mechanisms of IRF5 regulation during HCV infection and address the functional implications of its modulation and signaling in HCV pathogenesis. Findings from these studies will identify new molecular targets to combat chronic HCV infection.